Angiogenesis is a process of new blood vessels growing from pre-existing vessels. While it is a normal and vital physiological process during growth and development, it is often the transition of tumors from a dormant to a malignant state. In this case, tumor angiogenesis refers to the ability of a tumor to stimulate new blood vessel formation, which is a critical step that enables tumor expansion, local invasion, and dissemination through delivery of oxygen and nutrients, in addition to production of growth factors.
Angiogenesis is a well-controlled process during tumor formation, which is regulated by angiogenic, growth, and survival factors that are secreted by the malignant cells as well as other cells within the tumor microenvironment. Two prominent angiogenic factors include vascular endothelial growth factor (VFGF) family members and angiopoietins.
The angiopoietins are growth factors that modulate the processes of physiological angiogenesis and pathological neovascularization. They signal through Tie-2, a tyrosine receptor kinase present in endothelial cells. Angiopoietin family proteins in human so far include angiopoetin 1, angiopoietin 2, angiopoietin 4, angiopoietin like protein 1 (angiopoitein 3), angiopoietin like protein 2, angiopoietin like protein 3 (angiopoietin 5), angiopoietin like protein 4, angiopoietin like protein 5, angiopoietin like protein 6 and angiopoietin like protein 7.
The role of angiopoietins 1 (Ang1) and 2 (Ang2) in angiogenesis has been implicated by multiple reports. Both angiopoietins 1 and 2 are expressed at tumor vasculature (Stratmann et al., 1998). Coexpression of Ang1 and VEGF-A had an additive effect on angiogenesis and resulted in leakage resistant vessels (Thurston et al., 1999). Mice deficient of Ang1 had impaired vascular function, leading to embryonic death of the mice (Suri et al., 1996) while transgenic overexpression or gene transfer of angiopoietin 1 enhances vessel formation (Suri et al., 1998). Tie-2 knock-out mice showed similar phenotypes of the knock-out mice of angiopoietin 1, which suggests that Tie-2 activation by angiopoietin 1 mediates remodeling and stabilization of developing vessels (Suri et al., 1996).
Angiopoietin 2 is expressed only at sites of vascular remodeling in humans, such as placenta, ovary and uterus. It is mainly secreted by endothelial cells at the sites of vascular remodeling and acts in an autocrine manner. In the presence of VEGF-A, Angiopoietin 2 promotes vascular sprouting and destabilizes blood vessels by disrupting interactions between endothelial cells and matrix, thus enhancing VEGF stimulation (Holash et al., 1999). Angiopoietin 2 also can act as an apoptosis survival factor for endothelialcells during serum deprivation (Kim et al., 2000). Furthermore, upregulation of Angiopoietin 2 correlates with the metastasis and malignancy of various types of human cancers such as breast cancer, metastatic melanoma and lung cancer (Schliemann et al., 2007; Scholz et al., 2007; Park et al., 2007). Local production of Angiopoietin-2 has been identified as an early marker of glioma- and glioblastoma-induced neovascularization (Zagzag et al., 1999; Stratmann et al., 1998). More interestingly, upregulation of angiopoietins 1 and 2 has been shown to be a part of “angiogenic rescue” when VEGF mediated angiogenesis is blocked during tumor progression, resulting in acceleration of metastasis (Casanovas et al., 2005; Ebos et al., 2009; Huang et al., 2009; Paez-Ribes et al., 2009).
Given the role of angiopoietins 1 and 2 in angiogenesis, therapeutics against angiopoietins 1 and 2 might provide a benefit to patients with cancer such as, but not limited to, leukemia, lymphoma, and solid cancers, as well as to other non-neoplastic angiogenesis diseases such as, but not limited to, retinopathies, arthritis, atherosclerosis, respiratory disease, obesity, diabetes, asthma, liver regeneration, pulmonary hypertension, and psoriasis.